Multiple sclerosis (MS) is a neurological disease of major socioeconomic importance with a suspected virus etiology. Theiler's murine encephalomyelitis virus (TMEV) provides one of the most relevant of the few available experimental animal models of virus-induced demyelination for the following reasons: a) chronic pathological involvement is limited to the white matter of the central nervous system (CNS); b) myelin breakdown leads to clinical disease; c) TMEV persists in the CNS for the life of the mouse; and, d) demyelination appears to be immune-mediated. Our studies during the initial grant period have defined genetic loci contributing to disease susceptibility, established an immune- mediated basis for the development of TMEV-induced demyelinating disease, and defined a critical role for MHC class Il-restricted, virus-specific DTH responses in the demyelinating process. We have also demonstrated that chronic CNS demyelination can occur in the apparent absence of neuroantigen-specific autoimmune responses against the major myelin antigens. In addition, our studies have laid the groundwork for future studies on nonspecific (monoclonal antibody therapy) and specific (virus-specific tolerance induction) means of regulating virus and neuroantigen-specific CMI responses. Using in vivo-derived T cells and in vitro propagated T cell clones/hybrids, we propose to continue our research on defining the effector phenotype and epitope-specificity of the TMEV-specific T cell repertoire involved in the demyelinating process. We will also continue our studies examining the effects of and mechanisms responsible for both: nonspecific regulation of disease induction via therapy with monoclonal antibodies directed against MHC class I- and class Il-restricted T cell subsets, T cell activation antigens, and T cell lymphokines; and, specific regulation of virus-specific immunity and disease induction via TMEV-specific tolerance/suppressor T cell induction. Lastly, we will continue our investigation into the possible role of neuroantigen-specific autoimmune responses in the TMEV-induced demyelinating process. These studies should lead to a definitive understanding of the role of T cell-mediated immune responses in persistent virus induced demyelinating processes and may be applicable to the understanding of the etiology and treatment of MS.